Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma

X Wang, X Cao, R Sun, C Tang, A Tzankov, J Zhang, GC Manyam, M Xiao, Y Miao, K Jabbar, X Tan, Y Pang, C Visco, Y Xie, K Dybkaer, A Chiu, A Orazi, Y Zu, G Bhagat, KL Richards & 16 others ED Hsi, WWL Choi, JH van Krieken, J Huh, M Ponzoni, AJM Ferreri, MB Møller, BM Parsons, JN Winter, MA Piris, S Li, RN Miranda, LJ Medeiros, Y Li, ZY Xu-Monette, KH Young

Research output: Contribution to journalArticle

Abstract

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell–like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation. © 2017 The Authors
Original languageEnglish
Pages (from-to)574-593
Number of pages20
JournalNeoplasia (United States)
Volume20
Issue number6
DOIs
Publication statusPublished - 2018

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Lymphoma, Large B-Cell, Diffuse
Sequence Deletion
Survival
PTEN Phosphohydrolase
Messenger RNA
Mutation
Gene Deletion
MicroRNAs
Epigenomics
Genes
Cell Differentiation
Lymphoma
Neoplasms
B-Lymphocytes
Up-Regulation
Down-Regulation
Central Nervous System

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Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma. / Wang, X; Cao, X; Sun, R; Tang, C; Tzankov, A; Zhang, J; Manyam, GC; Xiao, M; Miao, Y; Jabbar, K; Tan, X; Pang, Y; Visco, C; Xie, Y; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; Winter, JN; Piris, MA; Li, S; Miranda, RN; Medeiros, LJ; Li, Y; Xu-Monette, ZY; Young, KH.

In: Neoplasia (United States), Vol. 20, No. 6, 2018, p. 574-593.

Research output: Contribution to journalArticle

Wang, X, Cao, X, Sun, R, Tang, C, Tzankov, A, Zhang, J, Manyam, GC, Xiao, M, Miao, Y, Jabbar, K, Tan, X, Pang, Y, Visco, C, Xie, Y, Dybkaer, K, Chiu, A, Orazi, A, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Choi, WWL, van Krieken, JH, Huh, J, Ponzoni, M, Ferreri, AJM, Møller, MB, Parsons, BM, Winter, JN, Piris, MA, Li, S, Miranda, RN, Medeiros, LJ, Li, Y, Xu-Monette, ZY & Young, KH 2018, 'Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma', Neoplasia (United States), vol. 20, no. 6, pp. 574-593. https://doi.org/10.1016/j.neo.2018.03.002
Wang, X ; Cao, X ; Sun, R ; Tang, C ; Tzankov, A ; Zhang, J ; Manyam, GC ; Xiao, M ; Miao, Y ; Jabbar, K ; Tan, X ; Pang, Y ; Visco, C ; Xie, Y ; Dybkaer, K ; Chiu, A ; Orazi, A ; Zu, Y ; Bhagat, G ; Richards, KL ; Hsi, ED ; Choi, WWL ; van Krieken, JH ; Huh, J ; Ponzoni, M ; Ferreri, AJM ; Møller, MB ; Parsons, BM ; Winter, JN ; Piris, MA ; Li, S ; Miranda, RN ; Medeiros, LJ ; Li, Y ; Xu-Monette, ZY ; Young, KH. / Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma. In: Neoplasia (United States). 2018 ; Vol. 20, No. 6. pp. 574-593.
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T1 - Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma

AU - Wang, X

AU - Cao, X

AU - Sun, R

AU - Tang, C

AU - Tzankov, A

AU - Zhang, J

AU - Manyam, GC

AU - Xiao, M

AU - Miao, Y

AU - Jabbar, K

AU - Tan, X

AU - Pang, Y

AU - Visco, C

AU - Xie, Y

AU - Dybkaer, K

AU - Chiu, A

AU - Orazi, A

AU - Zu, Y

AU - Bhagat, G

AU - Richards, KL

AU - Hsi, ED

AU - Choi, WWL

AU - van Krieken, JH

AU - Huh, J

AU - Ponzoni, M

AU - Ferreri, AJM

AU - Møller, MB

AU - Parsons, BM

AU - Winter, JN

AU - Piris, MA

AU - Li, S

AU - Miranda, RN

AU - Medeiros, LJ

AU - Li, Y

AU - Xu-Monette, ZY

AU - Young, KH

PY - 2018

Y1 - 2018

N2 - PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell–like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation. © 2017 The Authors

AB - PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell–like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation. © 2017 The Authors

U2 - 10.1016/j.neo.2018.03.002

DO - 10.1016/j.neo.2018.03.002

M3 - Article

VL - 20

SP - 574

EP - 593

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 6

ER -